European Patent Application No. 004 913 as laid open describes inter alia a process for the production of 17C-steroid-.alpha.-propionic acid compounds, particularly 3-oxopregna-4-ene-20-carboxylic acid (.DELTA.4-BNC) and/or 3-oxopregna-1,4-dien-20-carboxylic acid (.DELTA.1,4-BNC), by microbial side chain degradation on 17C-side chain steroid substrates. By using microorganism defect mutants grown and selected in a certain manner, which give steroid compounds containing the 17C-.alpha.-propionic acid residue, even in the absence of inhibitors which inhibit degradation of the steroid ring and/or growth, it is possible to obtain .DELTA.4-BNC and, in particular, .DELTA.1,4-BNC in commercial quantities. Another embodiment of this process is described in European Patent Application No. 0015 308.
These BNC compounds obtained by the side chain degradation of sterols (.DELTA.4-BNC and .DELTA.1,4-BNC) contain a functional group in only the 3-position of the ring system. However, all pharmacologically active corticosteroids contain additional oxygen functions. The 11,17- and 21-positions are particularly important in this respect. Normally some of these oxygen functions are chemically introduced, including, in particular, the 17- and 21-positions.
By contrast, oxidation of the 11-position in steroid compounds is preferably carried out microbially. Several microbial steroid oxidations in the 11-position are described in the specialist literature. In this connection, reference is made to the following publications and to the original articles cited therein:
(1) F. Drawert "Biosynthese von Hydroxy-Verbindungen (Biosynthesis of Hydroxy Compounds);" PA1 (2) Houben-Weyl "Methoden der organischen Chemie" (1978) 6/ld, pp. 378-388; PA1 (3) T. H. Stoudt, Adv. Appl. Microbial 2 (1960), pp. 190-195, and PA1 (4) W. Charney and H. L. Herzog "Microbial Transformations of Steroids" Academic Press (1967), New York, page 29. PA1 (a) recovery of the azide and heating to give the C-20-isocyanate by the elimination of nitrogen and, optionally, the C-20-isocyanate thus obtained is converted into the C-20-carbamate or the C-20-amine, and PA1 (b) hydrolyzing the azide by heating in the presence of an aqueous acid with elimination of nitrogen into the C20-amine,
The microbial 11-hydroxylation of a variety of steroid compounds and the synthesis products obtained are described in these publications with numerous references to certain microorganism strains, particularly from the class of fungi.
The 11 .beta.-hydroxyl or 11-oxo configuration is generally required for strong pharmacological activity. Steroids hydroxylated in the 11.beta.-position are obtained either by using microorganism strains which introduce a hydroxyl group of the type in question stereoselectively or by using other microorganisms which hydroxylate in the 11.beta.-position either predominantly or completely stereoselectively. In this case, the 11.beta.-hydroxylated steroids are obtained by chemical oxidation to the 11-ketone in a first step, followed by reduction with a suitable reducing agent. The 11.beta.-hydroxy compound can be formed stereoselectively. So far as the relevant literature on this subsequent chemical transformation is concerned, reference is made, for example, to L. F. Fieser, M. Fieser "Steroide (Steroids)," Verlag Chemie (Weinheim 1961), page 73 et seq. and to the original literature reference cited therein, J. Am. Chem. Soc. 77, 4436 (1955).
BNC-compounds having an oxygen function in the 11-position are described in DE-OS No. 28 39 033 which relates in particular to the production of 11.alpha.- and/or .beta.-hydroxy .DELTA.1,4-BNC and 11-keto-.DELTA.1,4-BNC by microbial oxidation of the corresponding BNC-compounds with hydrogen in the 11-position.